Journal of Alzheimer's Disease - Volume 94, issue 3

Article Type: Announcement

DOI: 10.3233/JAD-239005

Citation: Journal of Alzheimer's Disease, vol. 94, no. 3, pp. 859-860, 2023

Authors: Bayram, Ece | Holden, Samantha K. | Fullard, Michelle | Armstrong, Melissa J.

Article Type: Review Article

Abstract: Lewy body dementia is the third most common and costliest type of dementia. It is an umbrella term for dementia with Lewy bodies and Parkinson’s disease dementia, both of which place a substantial burden on the person and society. Recent findings outline ethnoracial differences in dementia risk. Delayed and misdiagnosis across ethnoracial groups contribute to higher levels of burden. In this context, we aimed to summarize current knowledge, gaps, and unmet needs relating to race and ethnicity in Lewy body dementia. In this narrative review, we provide an overview of studies on Lewy body dementia focusing on differences across ethnoracial …groups and outline several recommendations for future studies. The majority of the findings comparing different ethnoracial groups were from North American sites. There were no differences in clinical prevalence and progression across ethnoracial groups. Compared to people identifying as non-Hispanic White, co-pathologies were more common and clinical diagnostic accuracy was lower for people identifying as Black. Co-morbidities (e.g., diabetes, hypertension) were more common and medication use rates (e.g., antidepressants, antiparkinsonian agents) were lower for people identifying as Black or Hispanic compared to people identifying as White. More than 90% of clinical trial participants identified as non-Hispanic White. Despite increasing efforts to overcome disparities in Alzheimer’s disease and related dementias, inclusion of individuals from minoritized communities in Lewy body dementia studies continues to be limited and the findings are inconclusive. Representation of diverse populations is crucial to improve the diagnostic and therapeutic efforts in Lewy body dementia. Show more

Keywords: Alzheimer’s disease, dementia, diversity, equity, ethnicity, inclusion, Lewy body disease, racial groups

DOI: 10.3233/JAD-230207

Citation: Journal of Alzheimer's Disease, vol. 94, no. 3, pp. 861-878, 2023

Authors: Panza, Francesco | Solfrizzi, Vincenzo | Sardone, Rodolfo | Dibello, Vittorio | Castellana, Fabio | Zupo, Roberta | Stallone, Roberta | Lampignano, Luisa | Bortone, Ilaria | Mollica, Anita | Berardino, Giuseppe | Ruan, Qingwei | Altamura, Mario | Bellomo, Antonello | Daniele, Antonio | Lozupone, Madia

Article Type: Review Article

Abstract:  In older age, frailty is a detrimental transitional status of the aging process featuring an increased susceptibility to stressors defined by a clinical reduction of homoeostatic reserves. Multidimensional frailty phenotypes have been associated with all-cause dementia, mild cognitive impairment (MCI), Alzheimer’s disease (AD), AD neuropathology, vascular dementia, and non-AD dementias. In the present article, we reviewed current evidence on the existing links among depressive and biopsychosocial frailty phenotypes and late-life cognitive disorders, also examining common pathways and mechanisms underlying these links. The depressive frailty phenotype suggested by the construct of late-life depression (LLD) plus physical frailty is poorly operationalized. The …biopsychosocial frailty phenotype, with its coexistent biological/physical and psychosocial dimensions, defines a biological aging status and includes motivational, emotional, and socioeconomic domains. Shared biological pathways/substrates among depressive and biopsychosocial frailty phenotypes and late-life cognitive disorders are hypothesized to be inflammatory and cardiometabolic processes, together with multimorbidity, loneliness, mitochondrial dysfunction, dopaminergic neurotransmission, specific personality traits, lack of subjective/objective social support, and neuroendocrine dysregulation. The cognitive frailty phenotype, combining frailty and cognitive impairment, may be a risk factor for LLD and vice versa, and a construct of depressive frailty linking physical frailty and LLD may be a good dementia predictor. Frailty assessment may enable clinicians to better target the pharmacological and psychological treatment of LLD. Given the epidemiological links of biopsychosocial frailty with dementia and MCI, multidomain interventions might contribute to delay the onset of late-life cognitive disorders and other adverse health-related outcomes, such as institutionalization, more frequent hospitalization, disability, and mortality. Show more

Keywords: Alzheimer’s disease, cognitive frailty, dementia, frailty, lifestyle, mild cognitive impairment, physical frailty, social frailty, vascular dementia

DOI: 10.3233/JAD-230312

Citation: Journal of Alzheimer's Disease, vol. 94, no. 3, pp. 879-898, 2023

Authors: Wang, Ge | Li, Daniel Y. | Vance, David E. | Li, Wei

Article Type: Systematic Review

Abstract: Background: Alcohol use disorder (AUD) is a worldwide problem. The AUD can take the form of hazardous drinking, binge drinking, or alcohol dependence. The effects of alcohol on cognition can be diverse and complex. Objective: Our study aimed to assess AUD as a risk factor for cognitive impairment. Methods: A literature search was conducted using major electronic databases of PubMed, EMBASE, and Web of Science. Abstracts were screened independently to include data from original research reports. The following keywords were used: alcohol abuse, cognitive impairment, Alzheimer’s disease, and dementia. In total, 767 abstracts were retrieved. After …removing the duplicates, 76 articles met the criteria for full-text review, of which 41 were included in this report. Results: People with AUD are seen from different geographical areas and cultures. AUD is associated with an increased risk of cognitive impairments, Alzheimer’s disease, and dementia, especially vascular dementia. In addition, AUD interacts with comorbidities increasing the risk of cognitive impairment. Conclusion: AUD is associated with an increased risk of cognitive impairments, which may have more than one underlying mechanism. Show more

Keywords: Alcohol use disorder, Alzheimer’s disease, cognitive impairment, dementia

DOI: 10.3233/JAD-230181

Citation: Journal of Alzheimer's Disease, vol. 94, no. 3, pp. 899-907, 2023

Authors: Saúde, Alexandra | Bouça-Machado, Raquel | Leitão, Mariana | Benedetti, Andrea | Ferreira, Joaquim J.

Article Type: Systematic Review

Abstract: Background: Physiotherapy has become increasingly relevant as a new therapeutic intervention for dementia. However, it is unclear which interventions are the most suitable. Objective: This study sought to summarize and critically appraise the evidence on physiotherapy interventions in dementia. Methods: A systematic review conducted using CENTRAL, MEDLINE, and PEDro databases, from their inception to July 2022, identified all experimental studies of dementia that included physiotherapy interventions. Results: Of 194 articles included, the most frequently used interventions were aerobic training (n  = 82, 42%), strength training (n  = 79, 41%), balance training (n  = 48, 25%), and stretching …(n  = 22, 11%). These were associated with a positive effect on several motor and cognitive outcomes. A total number of 1,119 adverse events were reported. Conclusion: Physiotherapy has several motor and cognitive benefits in dementia. Future research should focus on establishing a physiotherapy prescription protocol for people with mild cognitive impairment and for each stage of dementia. Show more

Keywords: Alzheimer’s disease, clinical exercise, dementia, motor function, physiotherapy

DOI: 10.3233/JAD-230463

Citation: Journal of Alzheimer's Disease, vol. 94, no. 3, pp. 909-917, 2023

Authors: Fu, Xin-Xin | Wei, Bin | Cao, Hai-Ming | Duan, Rui | Deng, Yang | Lian, Hui-Wen | Zhang, Ying-Dong | Jiang, Teng

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is the most common type of neurodegenerative disorder. There are few effective medications for halting the progression of AD. Telmisartan (TEL) is a widely used anti-hypertensive drug approved by FDA. Aside from treating hypertension, TEL has been revealed to provide protection against AD. However, the underlying mechanisms remain unclear. Objective: To investigate the mechanisms underlying the beneficial effects of TEL against AD. Methods: Eight-month-old APP/PS1 mice were administered with 5 mg/kg TEL once per day for 4 successive months. Nesting test, Y-maze test, and Morris water maze test were employed to assess the …cognitive and executive functions. Neuronal and synaptic markers, amyloid-β (Aβ) pathology, neuroinflammation, and oxidative stress in the brains were measured. Specifically, components involved in Aβ production and degradation pathway were analyzed to explore the mechanisms underlying the therapeutic effect of TEL against Aβ pathology. The primary microglia were used to uncover the mechanisms underlying the anti-inflammatory effects of TEL in AD. Additionally, the preventive effect of TEL against AD were investigated using 4-month-old APP/PS1 mice. Results: TEL treatment ameliorated cognitive and executive impairments, neuronal and synaptic injury, Aβ pathology, neuroinflammation, and oxidative stress in APP/PS1 mice. The favorable effects of TEL on Aβ pathology were achieved by inhibiting enzymatic Aβ production and facilitating enzymatic and autophagic Aβ degradation. Meanwhile, the anti-inflammatory effects of TEL were accomplished via microglial PPARγ /NLRP3 pathway. The administration of TEL prior to symptom onset prevented AD-related cognitive decline and neuropathologies. Conclusion: TEL represents a promising agent for AD prevention and treatment. Show more

Keywords: Alzheimer’s disease, amyloid-β pathology, autophagy, cognitive and executive impairments, neuroinflammation, neuronal and synaptic injury, NLRP3, oxidative stress, PPARγ , telmisartan

DOI: 10.3233/JAD-230133

Citation: Journal of Alzheimer's Disease, vol. 94, no. 3, pp. 919-933, 2023

Authors: Heger, Irene | Deckers, Kay | de Vugt, Marjolein | Verhey, Frans | Oenema, Anke | van Boxtel, Martin | Köhler, Sebastian

Article Type: Research Article

Abstract: Background: Health- and lifestyle factors account for a substantial part of all dementia cases, which opens the opportunity for primary prevention. However, the required behavioral change is complex and involves targeting multiple risk factors. mHealth interventions can potentially contribute to improving motivation in a low-cost and scalable way. Objective: To explore usage patterns, appreciation, and beliefs and attitudes regarding dementia risk reduction during the use of the MyBraincoach mobile app. Methods: Participants were community-dwelling middle-aged adults from the Netherlands and used either the standard (education) or extended (education+motivational triggers) app version for three months. Two panel …studies were combined in this paper. Chi-square tests, t -tests and linear mixed models were used, adjusted for age, sex, and education. Results: Of all participants (n  = 299, 50.2% male), 167 (55.9%) had installed the app. The most reported reason for non-use was technical problems (47%). Those who used the app were at baseline already more positive about dementia risk reduction than those who did not use the app. Of all users who completed the evaluation (n  = 102), 78.4% (n  = 80) stated that the app provided a positive approach towards brain health and 80.4% (n  = 82) felt better informed. Younger (<60y) and lower educated participants evaluated the app most positively. Conclusion: Usage of the app was low, but users showed more positive beliefs and attitudes regarding dementia risk reduction. Most users evaluated the app positively and stated to have gained knowledge on the topic. Improving the use of the app must keep high priority in future studies. Show more

Keywords: Alzheimer’s disease, awareness, dementia, mobile applications, primary prevention, protective factors, public health, risk assessment, risk factors, risk reduction behavior

DOI: 10.3233/JAD-230225

Citation: Journal of Alzheimer's Disease, vol. 94, no. 3, pp. 935-948, 2023

Authors: Zakharova, Alena | Kitamura, Kaori | Watanabe, Yumi | Kabasawa, Keiko | Takahashi, Akemi | Saito, Toshiko | Kobayashi, Ryosaku | Oshiki, Rieko | Takachi, Ribeka | Tsugane, Shoichiro | Yamazaki, Osamu | Watanabe, Kei | Nakamura, Kazutoshi

Article Type: Research Article

Abstract: Background: The association between body mass index (BMI) and dementia risk is heterogeneous across age groups and might be influenced by sex. Objective: This study aimed to clarify sex differences in the association between BMI and dementia risk in community-dwelling people. Methods: This cohort study with an 8-year follow-up targeted 13,802 participants aged 40–74 years at baseline in 2011–2013. A self-administered questionnaire requested information on body size, including height, weight, and waist circumference (the values of which were validated by direct measurement), socio-demographics, lifestyle, and disease history. BMI was calculated and categorized as < 18.5 (underweight), 18.5–20.6 (low-normal), …20.7–22.6 (mid-normal), 22.7–24.9 (high-normal), 25.0–29.9 (overweight), and≥30.0 kg/m2 (obese). Incident cases of dementia were obtained from the long-term care insurance database. A Cox proportional hazards model was used to calculate multivariable-adjusted hazard ratios (HRs). Results: The mean age of participants was 59.0 years. In men, higher BMI was associated with lower dementia risk (fully-adjusted p for trend = 0.0086). In women, the association between BMI and dementia risk was U-shaped; the “underweight,” “low-normal,” and “overweight” groups had a significantly higher risk (fully-adjusted HR = 2.12, 2.08, and 1.78, respectively) than the reference (“high-normal” group). These findings did not change after excluding dementia cases which occurred within the first four years of the follow-up period. Conclusion: Overweight/obese women, but not men, had an increased risk of dementia, suggesting that sex differences in adiposity might be involved in the development of dementia. Show more

Keywords: Alzheimer’s disease, body mass index, cohort study, dementia, risk factor, sex difference, waist circumference

DOI: 10.3233/JAD-230294

Citation: Journal of Alzheimer's Disease, vol. 94, no. 3, pp. 949-959, 2023

Authors: Kostev, Karel

Article Type: Article Commentary

Abstract: In this issue, Zakharova et al. report on important findings concerning the association between body mass index and dementia risk as related to sex. Concretely, underweight was strongly associated with dementia risk in men but not in women. We compare the results of this study with a recent publication by Jacob et al. and consider the role of sex in the association between body mass index and dementia.

Keywords: Alzheimer’s disease, body mass index, dementia, sex, underweight

DOI: 10.3233/JAD-230598

Citation: Journal of Alzheimer's Disease, vol. 94, no. 3, pp. 961-962, 2023

Authors: Cubero-Plazas, Laura | Sancho-Cantus, David | de la Rubia Ortí, José Enrique | Prieto-Contreras, Lucía | Forero-Rincón, Olga | Cunha-Pérez, Cristina

Article Type: Research Article

Abstract: Background: Dementia is one of the pathologies that has increased the most among the older population (mainly Alzheimer’s disease), and it has a direct impact on the quality of life (QoL), cognitive performance, and health of these patients. Family functionality can play a role in this QoL if these patients are not institutionalized. Objective: To analyze the role of family function in the QoL and health perception of non-institutionalized dementia patients, as well as related variables such as anxiety, depression, optimism, or pessimism. Methods: Cross-sectional study with a sample of 54 patients diagnosed with some type …of dementia, non-institutionalized, or in outpatient care, from different centers in the province of Valencia (Spain). The EQ-5D, MMSE, Apgar Family or general health, and Goldberg anxiety and depression questionnaires were utilized. Results: The correlation of the Apgar Family with the General Health Questionnaire-new onset problems variable (GHQ) and Chronicity and General Health Questionnaire-chronic problems (CGHQ) of the Goldberg Quality of Life questionnaire was statistically significant and negative (GHQ r  = –0.310; p  = 0.034. CGHQ r  = –0.363; p  = 0.012); as well as between Apgar Family and Anxiety-Depression (r  = –0.341; p  = 0.020). The correlation of the Apgar Family with the Life Orientation Test-Pessimism variable (LOT) was statistically significant and negative (r  = –0.270; p  = 0.061). Finally, severe dysfunction of Apgar Family has a negative correlation with self-perception of health (p  = 0.036 B  = –16.589) determined by the Visual Analogue Scale (VAS). Conclusion: Family functionality directly influences anxiety, depression, optimism, and pessimism. This could explain why family function is related to the QoL of patients and their self-perception of health. Show more

Keywords: Alzheimer’s disease, anxiety, dementia, depression, family dynamics, health perception, non-institutionalized elderly, quality of life

DOI: 10.3233/JAD-230324

Citation: Journal of Alzheimer's Disease, vol. 94, no. 3, pp. 963-975, 2023

Authors: Ortí-Casañ, Natalia | Wajant, Harald | Kuiperij, H. Bea | Hooijsma, Annelien | Tromp, Leon | Poortman, Isabelle L. | Tadema, Norick | de Lange, Julia H.E. | Verbeek, Marcel M. | De Deyn, Peter P. | Naudé, Petrus J.W. | Eisel, Ulrich L.M.

Article Type: Research Article

Abstract: Background: Tumor necrosis factor-alpha (TNF-α ) is a master cytokine involved in a variety of inflammatory and neurological diseases, including Alzheimer’s disease (AD). Therapies that block TNF-α proved ineffective as therapeutic for neurodegenerative diseases, which might be explained by the opposing functions of the two receptors of TNF (TNFRs): while TNFR1 stimulation mediates inflammatory and apoptotic pathways, activation of TNFR2 is related to neuroprotection. Despite the success of targeting TNFR2 in a transgenic AD mouse model, research that better mimics the human context is lacking. Objective: The aim of this study is to investigate whether stimulation of …TNFR2 with a TNFR2 agonist is effective in activating human TNFR2 and attenuating AD neuropathology in the J20xhuTNFR2-k/i mouse model. Methods: Transgenic amyloid-β (Aβ)-overexpressing mice containing a human extracellular TNFR2 domain (J20xhuTNFR2-k/i) were treated with a TNFR2 agonist (NewStar2). After treatment, different behavioral tests and immunohistochemical analysis were performed to assess different parameters, such as cognitive functions, plaque deposition, synaptic plasticity, or microglial phagocytosis. Results: Treatment with NewStar2 in J20xhuTNFR2-k/i mice resulted in a drastic decrease in plaque load and beta-secretase 1 (BACE-1) compared to controls. Moreover, TNFR2 stimulation increased microglial phagocytic activity, leading to enhanced Aβ clearance. Finally, activation of TNFR2 rescued cognitive impairments and improved synaptic plasticity. Conclusion: Our findings demonstrate that activation of human TNFR2 ameliorates neuropathology and improves cognitive functions in an AD mouse model. Moreover, our study confirms that the J20xhuTNFR2-k/i mouse model is suitable for testing human TNFR2-specific compounds. Show more

Keywords: Alzheimer’s disease, humanized mouse model, neurodegeneration, neuroinflammation, TNF, TNFR2 agonist

DOI: 10.3233/JAD-221230

Citation: Journal of Alzheimer's Disease, vol. 94, no. 3, pp. 977-991, 2023

Authors: Sandison, Heather | Callan, Nini G.L. | Rao, Rammohan V. | Phipps, John | Bradley, Ryan

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is a chronic condition marked by progressive objective cognitive impairment (OCI). No monotherapy has substantially altered disease progression, suggesting the disease is multifactorial and may require a multimodal therapeutic approach. Objective: We sought to determine if cognitive function in a sample with OCI would change in response to a multimodal, individualized care plan based on potential contributors to cognitive decline (e.g., nutritional status, infection, etc.). Methods: Participants (n  = 34) were recruited from the San Diego, CA area. The multimodal intervention included lifestyle changes (i.e., movement, diet, and stress management), nutraceutical support, and …medications. It was delivered pragmatically over four clinical visits, and outcome measures were gathered at four study visits, occurring at baseline, one, three, and six months (primary endpoint). Study participants received weekly phone calls for nutrition support throughout study participation. Outcome measures included the Cambridge Brain Sciences (CBS) battery, and the Montreal Cognitive Assessment (MoCA). Results: At 6 months, mean MoCA scores improved from 19.6±3.1 to 21.7±6.2 (p  = 0.013). Significant improvement was observed in mean scores of the CBS memory domain [25.2 (SD 23.3) to 35.8 (SD 26.9); p  < 0.01] and CBS overall composite cognition score [24.5 (SD 16.1) to 29.7 (SD 20.5); p = 0.02]. All CBS domains improved. Conclusion: Multiple measures of cognitive function improved after six months of intervention. Our results support the feasibility and impact of a multimodal, individualized treatment approach to OCI, warranting further research. Show more

Keywords: Alzheimer’s disease, Cambridge Brain Sciences, clinical trial, dementia, mild cognitive impairment, Montreal Cognitive Assessment

DOI: 10.3233/JAD-230004

Citation: Journal of Alzheimer's Disease, vol. 94, no. 3, pp. 993-1004, 2023

Authors: Mao, He-Jiao | Zhang, Jiang-Xia | Zhu, Wen-Cheng | Zhang, Hao | Fan, Xiang-Min | Han, Fei | Ni, Jun | Zhou, Li-Xin | Yao, Ming | Tian, Feng | Su, Ning | Zhu, Yi-Cheng

Article Type: Research Article

Abstract: Background: The mechanism of gait disorder in patients with cerebral small vessel disease (CSVD) remains unclear. Limited studies have compared the effect of cerebral microbleeds (CMBs) and lacunes on gait disturbance in CSVD patients in different anatomical locations. Objective: To investigate the relationship of quantitative gait parameters with varied anatomically located MRI imaging markers in patients with CSVD. Methods: Quantitative gait tests were performed on 127 symptomatic CSVD patients all with diffuse distributed white matter hyperintensities (WMHs). CMBs and lacunes in regard to anatomical locations and burdens were measured. The correlation between CSVD imaging markers and …gait parameters was evaluated using general linear model analysis. Results: Presence of CMBs was significantly associated with stride length (β= –0.098, p  = 0.0272) and right step length (β= –0.054, p  = 0.0206). Presence of CMBs in basal ganglia (BG) was significantly associated with stride length and step length. Presence of CMBs in brainstem was significantly associated with gait parameters including stride length, step length, step height, and step width. Presence of lacunes in brainstem was significantly associated with gait speed (β= –0.197, p  = 0.0365). However, presence of lacunes in the other areas was not associated with worse gait performances. Conclusion: BG and brain stem located CMBs contributed to gait impairment in symptomatic CSVD patients. Show more

Keywords: Basal ganglia, brainstem, cerebral microbleeds, cerebral small vessel disease, quantitative gait parameters

DOI: 10.3233/JAD-230005

Citation: Journal of Alzheimer's Disease, vol. 94, no. 3, pp. 1005-1012, 2023

Authors: Falkenreck, Julia Maria | Kunkler, Michelle Celine | Ophey, Anja | Weigert, Hannah | Friese, Andrea | Jahr, Petra | Nelles, Gereon | Kalbe, Elke | Polidori, M. Cristina

Article Type: Research Article

Abstract: Background: Cognitive integrity is a fundamental driver of health. The exact structure of strategies against cognitive impairment is still under debate. Objective: To compare the short-term effects of a multicomponent cognitive training (BrainProtect) with those of general health counseling (GHC) on cognitive abilities and health-related quality of life (HRQoL) in healthy adults in Germany. Methods: In this parallel randomized controlled trial (RCT), 132 eligible cognitively healthy adults (age ≥50 years, Beck Depression Inventory ≤9/63; Montreal Cognitive Assessment ≥26/30) were randomized to either GHC (N = 72) or to intervention with BrainProtect (intervention group, IG; N = 60). IG participants received …8 weekly sessions of 90 min of the group-based BrainProtect program focusing on executive functions, concentration, learning, perception, and imagination, plus nutritional and physical exercise units. Before and after intervention, all participants underwent neuropsychological testing and HRQoL evaluation, blinded for pretest. Results: No significant training effect was observed for the primary endpoint of global cognition as assessed by CERAD-Plus-z Total Score (p  = 0.113; η p2  = 0.023). Improvements in several cognitive subtests were shown in the IG (N = 53) compared to the GHC (N = 62) without adverse events. Differences reached significance for verbal fluency (p  = 0.021), visual memory (p  = 0.013), visuo-constructive functions (p  = 0.034), and HRQoL (p  = 0.009). Significance was lost after adjustment, though several changes were clinically relevant. Conclusion: BrainProtect did not significantly impact global cognition in this RCT. Nevertheless, the results of some outcomes indicate clinically meaningful changes, so that a strengthening of the cognitive performance by BrainProtect cannot be excluded. Further studies with larger sample size are needed to confirm these findings. Show more

Keywords: Alzheimer’s disease, cognitive integrity, cognitive training, healthy aging, prevention

DOI: 10.3233/JAD-220619

Citation: Journal of Alzheimer's Disease, vol. 94, no. 3, pp. 1013-1034, 2023

Authors: Chwa, Won Jong | Lopez, Oscar L. | Longstreth Jr, W.T. | Dai, Weiying | Raji, Cyrus A.

Article Type: Research Article

Abstract: Background: Aging and Alzheimer’s disease (AD) are characterized by widespread cortical and subcortical atrophy. Though atrophy patterns between aging and AD overlap considerably, regional differences between these two conditions may exist. Few studies, however, have investigated these patterns in large community samples. Objective: Elaborate longitudinal changes in brain morphometry in relation to aging and cognitive status in a well-characterized community cohort. Methods: Clinical and neuroimaging data were compiled from 72 participants from the Cardiovascular Health Study-Cognition Study, a community cohort of healthy aging and probable AD participants. Two time points were identified for each participant with …a mean follow-up time of 5.36 years. MRI post-processing, morphometric measurements, and statistical analyses were performed using FreeSurfer, Version 7.1.1. Results: Cortical volume was significantly decreased in the bilateral superior frontal, bilateral inferior parietal, and left superior parietal regions, among others. Cortical thickness was significantly reduced in the bilateral superior frontal and left inferior parietal regions, among others. Overall gray and white matter volumes and hippocampal subfields also demonstrated significant reductions. Cortical volume atrophy trajectories between cognitively stable and cognitively declined participants were significantly different in the right postcentral region. Conclusion: Observed volume reductions were consistent with previous studies investigating morphometric brain changes. Patterns of brain atrophy between AD and aging may be different in magnitude but exhibit widespread spatial overlap. These findings help characterize patterns of brain atrophy that may reflect the general population. Larger studies may more definitively establish population norms of aging and AD-related neuroimaging changes. Show more

Keywords: Aging, Alzheimer’s disease, cognition, cognitive dysfunction, neuroimaging

DOI: 10.3233/JAD-230080

Citation: Journal of Alzheimer's Disease, vol. 94, no. 3, pp. 1035-1045, 2023

Authors: Caillaud, Marie | Maltezos, Samantha | Hudon, Carol | Mellah, Samira | Belleville, Sylvie

Article Type: Research Article

Abstract: Background: Subjective cognitive decline (SCD) was proposed to identify older adults who complain about their memory but perform within a normal range on standard neuropsychological tests. Persons with SCD are at increased risk of dementia meaning that some SCD individuals experience subthreshold memory decline due to an underlying progression of Alzheimer’s disease (AD). Objective: Our main goal was to determine whether hippocampal volume and APOE4 , which represent typical AD markers, predict inter-individual differences in memory performance among SCD individuals and can be used to identify a meaningful clinical subgroup. Methods: Neuropsychological assessment, structural MRI, and …genetic testing for APOE4 were administered to one hundred and twenty-five older adults over the age of 65 from the CIMAQ cohort: 66 SCD, 29 individuals with mild cognitive impairment (MCI), and 30 cognitively intact controls (CTRLS). Multiple regression models were first used to identify which factor (hippocampal volume, APOE4 allele, or cognitive reserve) best predicted inter-individual differences in a Face-name association memory task within the SCD group. Results: Hippocampal volume was found to be the only and best predictor of memory performance. We then compared the demographic, clinical and cognitive characteristics of two SCD subgroups, one with small hippocampal volume (SCD/SH) and another with normal hippocampal volume (SCD/NH), with MCI and CTRLS. SCD/SH were comparable to MCI on neuropsychological tasks evaluating memory (i.e., test of delayed word recall), whereas SCD/NH were comparable to CTRLS. Conclusion: Thus, using hippocampal volume allows identification of an SCD subgroup with a cognitive profile consistent with a higher risk of conversion to AD. Show more

Keywords: Alzheimer’s disease, hippocampal volume, mild cognitive impairment, neuropsychology, subjective cognitive decline

DOI: 10.3233/JAD-230131

Citation: Journal of Alzheimer's Disease, vol. 94, no. 3, pp. 1047-1056, 2023

Authors: Hautecloque-Raysz, Geoffroy | Sellal, François | Bousiges, Olivier | Phillipi, Nathalie | Blanc, Frédéric | Cretin, Benjamin

Article Type: Research Article

Abstract: Background: The medium term outcome (over more than one year) of epileptic prodromal AD (epAD) patients treated with antiseizure medications (ASMs) is unknown in terms of seizure response, treatment tolerability, and cognitive and functional progression. Objective: To describe such medium term outcome over a mean of 5.1±2.1 years. Methods: We retrospectively compared 19 epAD patients with 16 non-epileptic prodromal AD (nepAD) patients: 1) at baseline for demographics, medical history, cognitive fluctuations (CFs), psychotropic medications, MMSE scores, visually rated hippocampal atrophy, CSF neurodegenerative biomarkers, and standard EEG recordings; 2) during follow-up (FU) for psychotropic medications, MMSE progression, …and conversion to dementia. In the epAD group, we analyzed baseline and FU types of seizures as well as each line of ASM with the corresponding efficacy and tolerability. Results: At baseline, the epAD group had more CFs than the nepAD group (58% versus 20%, p  = 0.03); focal impaired awareness seizures were the most common type (n  = 12, 63.1%), occurring at a monthly to quarterly frequency (89.5%), and were well controlled with monotherapy in 89.5% of cases (including 63.1% seizure-free individuals). During FU, treated epAD patients did not differ significantly from nepAD patients in MMSE progression or in conversion to dementia. Conclusion: Epilepsy is commonly controlled with ASMs over the medium term in epAD patients, with similar functional and cognitive outcomes to nepAD patients. Pathophysiologically, epilepsy is likely to be an ASM-modifiable cognitive aggravating factor at this stage of AD. Show more

Keywords: Alzheimer’s disease, antiseizure medications, cerebrospinal fluid, late-onset epilepsy, mild cognitive impairment

DOI: 10.3233/JAD-221197

Citation: Journal of Alzheimer's Disease, vol. 94, no. 3, pp. 1057-1074, 2023

Authors: Vossel, Keith

Article Type: Article Commentary

Abstract: Epileptic activity is known to exacerbate Alzheimer’s disease (AD) pathology and worsen disease course. However, few studies have assessed whether treating epileptic activity with antiseizure drugs (ASDs) can improve patient outcomes. The current study by Hautecloque-Raysz et al. shows that patients with prodromal AD and epilepsy (epAD) fare well with ASD treatment, achieving seizure control in a large majority of cases using low dosage ASDs in monotherapy. Compared to slowly progressing AD patients without epilepsy, treated epAD patients experienced a similarly slow cognitive decline. These results suggest that ASDs that suppress seizures can improve outcomes in AD patients with epileptic …activity. Show more

Keywords: Alzheimer’s disease, antiseizure drugs, epilepsy, epileptic activity, mild cognitive impairment

DOI: 10.3233/JAD-230613

Citation: Journal of Alzheimer's Disease, vol. 94, no. 3, pp. 1075-1077, 2023

Authors: Beauchet, Olivier | Matskiv, Jacqueline | Gaudreau, Pierrette | Allali, Gilles | Vaillant-Ciszewicz, Anne-Julie | Guerin, Olivier | Gros, Auriane

Article Type: Research Article

Abstract: Background: Frailty is associated with an increased risk of major neurocognitive disorders (MNCD). Objective: This study aims to compare the Fried physical model and the CARE deficit accumulation model for their association with incident major neurocognitive disorders (MNCD), and to examine how the addition of cognitive impairment to these frailty models impacts the incidence in community-dwelling older adults. Methods: A subset of community dwellers (n  = 1,259) who participated in the “Quebec Longitudinal Study on Nutrition and Successful Aging” (NuAge) were selected in this Elderly population-based observational cohort study with 3 years of follow-up. Fried and CARE …frailty stratifications into robust, pre-frail and frail groups were performed using the NuAge baseline assessment. Incident MNCD (i.e., Modified Mini Mental State (3MS) score < 79/100 and Instrumental Activity Daily Living (IADL) score < 6/8) were collected each year over a 3-year follow-up period. Results: A greater association with incident MNCD of the CARE frail state was observed with an increased predictive value when combined with cognitive impairment in comparison to Fried’s one, the highest incidences being observed using the robust state as the reference. Results with the Fried frail state were more heterogenous, with no association with the frail state alone, whereas cognitive impairment alone showed the highest significant incidence. Conclusion: The association of the CARE frail state with cognitive impairment increased the predictive value of MNCD, suggesting that the CARE frailty model may be of clinical interest when screening MCND in the elderly population. Show more

Keywords: Aging, Alzheimer’s disease, cognitive impairment, cohort study, community-dwellers, frailty

DOI: 10.3233/JAD-230006

Citation: Journal of Alzheimer's Disease, vol. 94, no. 3, pp. 1079-1092, 2023

Authors: Chen, Weineng | Lin, Cha | Su, Fengjuan | Fang, Yingying | Liu, Ganqiang | Chen, Yu-Chian | Zhou, Xianbo | Yao, Xiaoli | Ashford, Curtis B. | Li, Feng | Ashford, J. Wesson | Fu, Qing-Ling | Pei, Zhong

Article Type: Research Article

Abstract: Background: Accessible measurements for the early detection of mild cognitive impairment (MCI) due to Alzheimer’s disease (AD) are urgently needed to address the increasing prevalence of AD. Objective: To determine the benefits of a composite MemTrax Memory Test and AD-related blood biomarker assessment for the early detection of MCI-AD in non-specialty clinics. Methods: The MemTrax Memory Test and Montreal Cognitive Assessment were administered to 99 healthy seniors with normal cognitive function and 101 patients with MCI-AD; clinical manifestation and peripheral blood samples were collected. We evaluated correlations between the MemTrax Memory Test and blood biomarkers using …Spearman’s rank correlation analyses and then built discrimination models using various machine learning approaches that combined the MemTrax Memory Test and blood biomarker results. The models’ performances were assessed according to the areas under the receiver operating characteristic curve. Results: The MemTrax Memory Test and Montreal Cognitive Assessment areas under the curve for differentiating patients with MCI-AD from the healthy controls were similar. The MemTrax Memory Test strongly correlated with phosphorylated tau 181 and amyloid-β42/40 . The area under the curve for the best composite MemTrax Memory Test and blood biomarker model was 0.975 (95% confidence interval: 0.950–0.999). Conclusion: Combining MemTrax Memory Test and blood biomarker results is a promising new technique for the early detection of MCI-AD. Show more

Keywords: Alzheimer’s disease, biomarkers, cognitive dysfunction, neuropsychological tests

DOI: 10.3233/JAD-230182

Citation: Journal of Alzheimer's Disease, vol. 94, no. 3, pp. 1093-1103, 2023

Authors: Belan, Ariella Fornachari Ribeiro | Pais, Marcos Vasconcelos | Camargo, Marina von Zuben de Arruda | Sant’Ana, Livea Carla Fidalgo Garcêz | Radanovic, Marcia | Forlenza, Orestes Vicente

Article Type: Research Article

Abstract: Background: The assessment of language changes associated with visual search impairment can be an important diagnostic tool in the Alzheimer’s disease (AD) continuum. Objective: Investigate the performance of an eye-tracking assisted visual inference language task in differentiating subjects with mild cognitive impairment (MCI) or AD dementia from cognitively unimpaired older adults (controls). Methods: We assessed a group of 95 older adults (49 MCI, 18 mild dementia due to AD, and 28 controls). The subjects performed the same task under multiple experimental conditions which generate correlated responses that need to be taken into account. Thus, we performed …a non-parametric repeated measures ANOVA model for verbal answers, and a linear mixed model (LMM) or its generalized version for the analysis of eye tracking variables. Results: Significant differences were found in verbal answers across all diagnostic groups independently of type of inference, i.e., logic or pragmatic. Also, eye-tracking parameters were able to discriminate AD from MCI and controls. AD patients did more visits to challenge stimulus (Control-AD, –0.622, SE = 0.190, p  = 0.004; MCI-AD, –0.514, SE = 0.173, p  = 0.011), more visits to the correct response stimulus (Control-AD, –1.363, SE = 0.383, p  = 0.002; MCI-AD, –0.946, SE = 0.349, p  = 0.022), more fixations on distractors (Control-AD, –4.580, SE = 1.172, p  = 0.001; MCI-AD, –2.940, SE = 1.070, p  = 0.020), and a longer time to first fixation on the correct response stimulus (Control-AD, –0.622, SE = 0.190, p  = 0.004; MCI-AD, –0.514, SE = 0.173, p  = 0.011). Conclusion: The analysis of oculomotor behavior along with language assessment protocols may increase the sensitivity for detection of subtle deficits in the MCI-AD continuum, representing an important diagnostic tool. Show more

Keywords: Alzheimer’s disease, cognitive impairment, eye movement, eye-tracking, visual inferences, visual search impairment

DOI: 10.3233/JAD-230250

Citation: Journal of Alzheimer's Disease, vol. 94, no. 3, pp. 1105-1119, 2023

Authors: Kulminski, Alexander M. | Feng, Fan | Loiko, Elena | Nazarian, Alireza | Loika, Yury | Culminskaya, Irina

Article Type: Research Article

Abstract: Background: The lack of efficient preventive interventions against Alzheimer’s disease (AD) calls for identifying efficient modifiable risk factors for AD. As diabetes shares many pathological processes with AD, including accumulation of amyloid plaques and neurofibrillary tangles, insulin resistance, and impaired glucose metabolism, diabetes is thought to be a potentially modifiable risk factor for AD. Mounting evidence suggests that links between AD and diabetes may be more complex than previously believed. Objective: To examine the pleiotropic architecture of AD and diabetes mellitus (DM). Methods: Univariate and pleiotropic analyses were performed following the discovery-replication strategy using individual-level data …from 10 large-scale studies. Results: We report a potentially novel pleiotropic NOTCH2 gene, with a minor allele of rs5025718 associated with increased risks of both AD and DM. We confirm previously identified antagonistic associations of the same variants with the risks of AD and DM in the HLA and APOE gene clusters. We show multiple antagonistic associations of the same variants with AD and DM in the HLA cluster, which were not explained by the lead SNP in this cluster. Although the ɛ 2 and ɛ 4 alleles played a major role in the antagonistic associations with AD and DM in the APOE cluster, we identified non-overlapping SNPs in this cluster, which were adversely and beneficially associated with AD and DM independently of the ɛ 2 and ɛ 4 alleles. Conclusion: This study emphasizes differences and similarities in the heterogeneous genetic architectures of AD and DM, which may differentiate the pathogenic mechanisms of these diseases. Show more

Keywords: Alzheimer’s disease, apolipoprotein E gene, diabetes, major histocompatibility complex, pleiotropy

DOI: 10.3233/JAD-230397

Citation: Journal of Alzheimer's Disease, vol. 94, no. 3, pp. 1121-1132, 2023

Authors: Jeong, Seong Ho | Cha, Jungho | Jung, Jin Ho | Yun, Mijin | Sohn, Young H. | Chung, Seok Jong | Lee, Phil Hyu

Article Type: Research Article

Abstract: Background: Clinical significance of additional occipital amyloid-β (Aβ) plaques in Alzheimer’s disease (AD) remains unclear. Objective: In this study, we investigated the effect of regional Aβ deposition on cognition in patients on the AD continuum, especially in the occipital region. Methods: We retrospectively reviewed the medical record of 208 patients with AD across the cognitive continuum (non-dementia and dementia). Multivariable linear regression analyses were performed to determine the effect of regional Aβ deposition on cognitive function. A linear mixed model was used to assess the effect of regional deposition on longitudinal changes in Mini-Mental State Examination …(MMSE) scores. Additionally, the patients were dichotomized according to the occipital-to-global Aβ deposition ratio (ratio ≤1, Aβ-OCC– group; ratio >1, Aβ-OCC+ group), and the same statistical analyses were applied for between-group comparisons. Results: Regional Aβ burden itself was not associated with baseline cognitive function. In terms of Aβ-OCC group effect, the Aβ-OCC+ group exhibited a poorer cognitive performance on language function compared to the Aβ-OCC– group. High Aβ retention in each region was associated with a rapid decline in MMSE scores, only in the dementia subgroup. Additionally, Aβ-OCC+ individuals exhibited a faster annual decline in MMSE scores than Aβ-OCC– individuals in the non-dementia subgroup (β= –0.77, standard error [SE] = 0.31, p  = 0.013). Conclusion: The present study demonstrated that additional occipital Aβ deposition was associated with poor baseline language function and rapid cognitive deterioration in patients on the AD continuum. Show more

Keywords: Alzheimer’s disease, amyloid, cognition, occipital lobe, prognosis

DOI: 10.3233/JAD-230187

Citation: Journal of Alzheimer's Disease, vol. 94, no. 3, pp. 1133-1144, 2023